This invention relates generally to a method for enhancing the delivery of xcex94-9-tetrahydrocannabinol (xe2x80x9cTHCxe2x80x9d) to the brain of a mammal in need of treatment with this drug, by administering water-soluble prodrugs of THC intranasally. More specifically, this invention relates to the enhancement of THC treatment by intranasal administration of water-soluble esters of THC. The invention is particularly useful as an anti-emetic, particulary to treat the nausea associated with anti-cancer chemotherapy.
The anti-emetic properties of THC are well-known. The lay press have advocated that marijuana (smoked) be made available for use as an anti-emetic, especially in cancer and AIDS patients who find it to be the only substance that controls their nausea while receiving chemotherapy. Unfortunately, marijuana smoke contains many of the carcinogenic substances that make tobacco smoke dangerous, and the toxicities associated with smoked marijuana are probably as great as those associated with tobacco smoking. 
Oral THC is commercially available as the prescription product Marinol(copyright) Capsules. However, the oral absorption of THC from Marinol(copyright) Capsules is very slow and inefficient. It is estimated that less than half the oral dose of THC is absorbed, and the anti-emetic effects are not seen clinically until the second day after administration has begun. Thus, Marinol(copyright) Capsules are not useful unless taken chronically.
On the other hand, THC is rapidly and efficiently absorbed from marijuana smoke. It is likely that this rapid absorption is responsible for its clinical usefulness, i.e., a patient can offset nausea by smoking marijuana after the nausea begins to occur. The absorption of a variety of drugs with a variety of chemical structures from the nasal cavity of humans is known to produce blood concentrations similar to those observed following intravenous administration.
At room temperature, THC exists as a gummy, semisolid mass, which has very poor aqueous solubility. The physical properties of THC cause difficulties in the formulation of dosage forms suitable for human consumption. Certain dosage forms, e.g., injectables, cannot be prepared because of the physical nature of THC. The oral administration of THC is inefficient and highly variable resulting in an on-off therapeutic response and frequent serious side effects. There is a tremendous need for an improved dosage form for THC. Since THC is too insoluble in water, it cannot be administered nasally, transdermally, buccally, or sublingually.
In view of the foregoing, it is apparent that there exists a need in the art for improved methods of delivery of THC for treatment of nausea and prevention of emesis, in particular in connection with anti-cancer chemotherapy.
Accordingly, since THC is too insoluble in water to be used in conventional intranasal formulations, it is an object of the present invention to provide a method for alleviating nausea comprising intranasal administration of water soluble prodrugs of THC. The prodrug esters of THC described herein are sufficiently water-soluble to allow the formulation of any desired dosage form and are more readily absorbed into the systemic circulation, i.e., are more bioavailable than THC itself.
An intranasal dosage form containing a water-soluble prodrug ester of THC that would rapidly deliver an effective does of THC to the blood following administration would have the same anti-emetic benefits as marijuana smoke but without the toxicities associated with smoke products.
It is a further aspect of this invention to provide a method for administering THC in a manner which significantly enhances plasma levels of THC, and thus its bioavailability, compared to prior art methods.
It is a further aspect of this invention to provide a method for administering THC which provides for enhanced delivery of THC directly to the central nervous system, its intended site of action.
In addition to intranasal dosage forms, the prodrug esters described in the present application also lend themselves to formulation into dosage forms designed to be administered orally, by injection, transdermally, or by any other conceivable routes. In particular, water-soluble derivatives that exist as crystalline solids would lend themselves readily to formulation into oral tablets, capsules, and liquids.
It is a still further aspect of this invention to provide a method for administering THC which minimizes the side-effects associated with conventional THC administration. This object has been achieved in the present invention by the nasal administration of water-soluble esters of THC.
It is a still further aspect of this invention to provide a method for administering THC which is equal or superior to intravenous administration in many respects, including effectiveness, but which avoids many of the problems associated with the intravenous route, including the xe2x80x9con-off effect,xe2x80x9d combined with superior ease of administration.
A further aspect of this invention is to provide a pharmaceutical composition suitable for intranasal administration, for treatment of nausea and emesis, particularly associated with anti-cancer chemotherapy. Accordingly, a composition according to the present invention comprises a water-soluble prodrug of THC and a pharmaceutically acceptable carrier therefor.
With the foregoing and other objects, advantages and features of the invention that will become hereinafter apparent, the nature of the invention may be more clearly understood by reference to the following detailed description of the preferred embodiments of the invention and to the appended claims.
The present inventors have discovered a novel method for the treatment of nausea and prevention of emesis, by the intranasal administration of a water-soluble prodrug of THC. This method offers significant clinical advantages over the prior art. More specifically, the inventors sought to provide a safe, effective and convenient treatment for nausea and vomiting associated with anti-cancer chemotherapy which comprises the administration of water-soluble prodrugs of THC intranasally, thus avoiding the side-effects associated with oral dosage forms.
A prodrug is a compound formed by chemical modification of a biologically active compound which will liberate the active compound in vivo by enzymatic or hydrolytic cleavage. Advantages of this approach include reduction of general cytotoxicity, better bioavailability of active drug or longer duration of action. Any water soluble prodrug of THC is useful in the practice of this present invention.
The inventors have found that intranasal administration of esters of THC, i.e., prodrugs of THC, are particularly preferred in the practice of the present invention. Intranasal administration of these compounds is as effective as oral or intravenous administration of THC, but may be conveniently and painlessly self-administered by the patient.
Preferred THC esters include alkyl, cycloalkyl, and aryl esters, particularly methyl, butyl, pentyl, cyclohexyl, and benzyl esters, and pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts of an acid group or an amino group include, but are not limited to, salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isothionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-tolylsulfonic acids, and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
In a preferred embodiment, a compound according to the present invention is a THC amine-ester prodrug having, for example, a structure according to Formula (I) 
wherein
n=1 to 10; and
R1 and R2 are both alkyl, or together are members of a saturated ring.
In an alternative embodiment, a compound according to the present invention is a hemiester THC prodrug having, for example, a structure according to Formula (II): 
wherein n 1 to 10.
In another alternative embodiment, a compound according to the present invention is a phosphate ester THC prodrug having, for example, a structure according to Formula (III): 
A still further aspect of this invention is a pharmaceutical composition of matter for treating nausea and vomiting that comprises at least one THC ester as described above, mixtures of THC esters thereof, and/or pharmaceutical salts thereof, and pharmaceutically acceptable carriers therefor. Such compositions are prepared in accordance with accepted pharmaceutical procedures, for example, as described in Remington""s Pharmaceutical Sciences, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pa., Eighteenth edition (1990).
For therapeutic use in a method of treating nausea, a THC ester, or its salt, can be conveniently administered in the form of a pharmaceutical composition containing a THC ester, or its salt, and a pharmaceutically acceptable carrier therefor. Suitable carriers are well known to those skilled in the art and vary with the desired form and mode of administration of the pharmaceutical composition. Typically, the carrier may be a liquid, suspension, semi-solid, or vaporizable carrier, or combinations thereof. In a preferred embodiment, the carrier is a pharmaceutically acceptable aqueous carrier.
The compound of the invention or its salt may be formulated together with the carrier into any desired unit dosage form. Unit dosage forms such as solutions, suspensions, and water-miscible semisolids are particularly preferred.
Each carrier must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient. The carrier must be biologically acceptable and inert, i.e., it must permit the body""s metabolic reactions to effectively transform the esters of this invention into THC. To prepare formulations suitable for intranasal administration, solutions and suspensions are sterilized and are preferably isotonic to blood.
The formulations may conveniently be presented in unit dosage form and may be prepared by any method known in the art. Such methods include the step of bringing the active ingredient into association with the carrier which itself may encompass one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. Various unit dose and multidose containers, e.g., sealed ampules and vials, may be used, as is well known in the art.
In addition to the ingredients particularly mentioned above, the formulations of this invention may also include other agents conventional in the art for this type of pharmaceutical formulation.
Also part of this invention is a method of treating nausea and preventing emesis, particularly that associated with anti-cancer chemotherapy, in a mammal, e.g., human, by treating that mammal with an effective amount of a THC ester intranasally. In this application patient will encompass any mammal suffering from nausea or vomiting, particularly a mammal undergoing anti-cancer chemotherapy.
The dosage of the THC esters, pharmaceutically acceptable salts thereof, or mixtures thereof, in the compositions of the invention administered to a patient will vary depending on several factors, including, but not limited to, the age, weight, and species of the patient, the general health of the patient, the severity of the symptoms, whether the composition is being administered alone or in combination with other agents, the incidence of side effects and the like. The desired dose may be administered as 1 to 6 or more subdoses administered at appropriate intervals throughout the day. The compounds may be administered repeatedly over a period of months or years, or it may be slowly and constantly infused to the patient. Higher and lower doses may also be administered.
The daily dose may be adjusted taking into account, for example, the above-identified variety of parameters. Typically, the present compositions may be administered in an amount of about 1 to 50 mg/kg body weight. However, other amounts may also be administered.
To achieve good plasma concentrations, the active compounds may be administered, for instance, by intranasal administration of an approximate 0.1 to 1M solution of the active ingredient, optionally in saline.
While it is possible for the active ingredient to be administered alone, it is preferably present as a pharmaceutical formulation. The formulations of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents.
The above method may be practiced by administration of the compounds by themselves or in a combination with other active ingredients in a pharmaceutical composition. Other therapeutic agents suitable for use herein are any compatible drugs that are effective by the same or other mechanisms for the intended purpose, or drugs that are complementary to those of the present agents. Agents effective against chemotherapy-induced emesis include D2/5HT3 antagonists such as substituted benzamides (e.g., metoclopramide, trimethobenzamide); 5HT3 antagonists (e.g., ondansetron, granisetron, tropisetron, dolasetron); D2 antagonists, such as the phenothiazines (e.g., chlorpromazine, perphenazine, proclorperazine, promethazine, thiethylperazine, triflupromazine), benzimidazole derivatives (e.g., domperidone), and butyrophenones (e.g., haloperidol, droperidol); corticosteroids (e.g., dexamethasone, methylprednisolone); and other cannabinoids (e.g., nabilone). The compounds utilized in combination therapy may be administered simultaneously, in either separate or combined formulations, or at different times than the present compounds, e.g., sequentially, such that a combined effect is achieved. The amounts and regime of administration will be adjusted by the practitioner, by preferably initially lowering their standard doses and then titrating the results obtained. The therapeutic method of the invention may be used in conjunction with other therapies as determined by the practitioner.